mln-8237 and Leiomyosarcoma

This two-stage Phase II study assessed the activity of single agent alisertib in patients with recurrent/persistent uterine leiomyosarcoma (uLMS).. Eligibility criteria included histologically-confirmed, recurrent or persistent uLMS, age≥18, 1-2 prior cytotoxic regimens, and RECIST version 1.1 measurable disease. The primary objective of the study was to evaluate the efficacy of alisertib through the frequency of patients with objective tumor responses and the frequency who survived event-free for at least 6months (EFS6). The endpoints for EFS were RECIST progression, death, or beginning a subsequent therapy. The null hypothesis jointly specified the probability of a patient experiencing a tumor response to less than or equal to 5% and the probability of a patient surviving event-free for at least 6months to less than or equal to 20%. A two-stage design was used with a target accrual of 23 patients for stage 1 and 47 pts. cumulative for stage 2. Confidence intervals do not correct for multiplicity.. Twenty-three patients were enrolled with two patients excluded on central histology review, yielding 21 eligible patients. Median age was 61years. Prior treatment was either 1 cytotoxic regimen (71.4%) or 2 (28.6%). The most common treatment related AEs (grade 3 or worse) were anemia Hensley et al. (2008a) , leukopenia Hensley et al. (2008b) , neutropenia Maki et al. (2007) , thrombocytopenia Huang et al. (2012) , mucositis Hensley et al. (2008a) , diarrhea Huang et al. (2012) , and palmer-planter syndrome Zivanovic et al. (2012) . There were no objective responses (0%; 90% CI: 0-10.4%). Best response was stable disease (38.1%); 12 patients had progressive disease (57.1%). EFS6 was 0% (90% CI: 0-10.4%). Median PFS and OS were 1.7 (90% CI: 1.4-3.2) and 14.5months (90% CI: 7.6 - NA), respectively.. Alisertib did not demonstrate clinically meaningful single agent activity in previously treated uLMS.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Azepines; Disease Progression; Disease-Free Survival; Female; Humans; Leiomyosarcoma; Middle Aged; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrimidines; Response Evaluation Criteria in Solid Tumors; Retreatment; Survival Rate; Uterine Neoplasms

Aurora kinase A (AURKA) is commonly overexpressed in sarcoma. The inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (alisertib) is a novel oral adenosine triphosphate-competitive AURKA inhibitor.. This Cancer Therapy Evaluation Program-sponsored phase II study of alisertib was conducted through the Alliance for Clinical Trials in Oncology (A091102). Patients were enrolled into histology-defined cohorts: (i) liposarcoma, (ii) leiomyosarcoma, (iii) undifferentiated sarcoma, (iv) malignant peripheral nerve sheath tumor, or (v) other. Treatment was alisertib 50 mg PO b.i.d. d1-d7 every 21 days. The primary end point was response rate; progression-free survival (PFS) was secondary. One response in the first 9 patients expanded enrollment in a cohort to 24 using a Simon two-stage design.. Seventy-two patients were enrolled at 24 sites [12 LPS, 10 LMS, 11 US, 10 malignant peripheral nerve sheath tumor (MPNST), 29 Other]. The median age was 55 years; 54% were male; 58%/38%/4% were ECOG PS 0/1/2. One PR expanded enrollment to the second stage in the other sarcoma cohort. The histology-specific cohorts ceased at the first stage. There were two confirmed PRs in the other cohort (both angiosarcoma) and one unconfirmed PR in dedifferentiated chondrosarcoma. Twelve-week PFS was 73% (LPS), 44% (LMS), 36% (US), 60% (MPNST), and 38% (Other). Grade 3-4 adverse events: oral mucositis (12%), anemia (14%), platelet count decreased (14%), leukopenia (22%), and neutropenia (42%).. Alisertib was well tolerated. Occasional responses, yet prolonged stable disease, were observed. Although failing to meet the primary RR end point, PFS was promising.. NCT01653028.

Topics: Adult; Aged; Aged, 80 and over; Aurora Kinase A; Azepines; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Leiomyosarcoma; Liposarcoma; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyrimidines

The significance of mTOR activation in uterine leiomyosarcoma (ULMS) and its potential as a therapeutic target were investigated. Furthermore, given that effective therapies likely require combination mTOR blockade with inhibition of other targets, coupled with recent observations suggesting that Aurora-A kinase (Aurk-A) deregulations commonly occur in ULMS, the preclinical impact of dually targeting both pathways was evaluated.. Immunohistochemical staining was used to evaluate expression of activated mTOR components in a large (>200 samples) ULMS tissue microarray. Effects of mTOR blockade (using rapamycin) and Aurk-A inhibition (using MLN8237) alone and in combination on human ULMS cell growth, cell-cycle progression, and apoptosis were assessed in cellular assays. Drug interactions were determined via combination index analyses. The antitumor effects of inhibitors alone or in combination were evaluated in vivo.. Enhanced mTOR activation was seen in human ULMS samples. Increased pS6RP and p4EBP1 expression correlated with disease progression; p4EBP1 was found to be an independent prognosticator of patient outcome. Rapamycin inhibited growth and cell-cycle progression of ULMS cell strains/lines in culture. However, only a cytostatic effect on tumor growth was found in vivo. Combining rapamycin with MLN8237 profoundly (and synergistically) abrogated ULMS cells' growth in culture; interestingly, these effects were seen only when MLN8237 was preadministered. This novel therapeutic combination and scheduling regimen resulted in marked tumor growth inhibition in vivo.. mTOR and Aurk-A pathways are commonly deregulated in ULMS. Preclinical data support further exploration of dual mTOR and Aurk-A therapeutic blockade for human ULMS.

Topics: Animals; Apoptosis; Aurora Kinase A; Aurora Kinases; Azepines; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Leiomyosarcoma; Mice; Protein Serine-Threonine Kinases; Pyrimidines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Heterologous; Uterine Neoplasms